Comparative studies of potential cancer biomarkers carbon-11 labeled MMP inhibitors (S)-2-(4′-[ 11C]methoxybiphenyl-4-sulfonylamino)-3-methylbutyric acid and N-hydroxy-(R)-2-[[(4′-[ 11C]methoxyphenyl)sulfonyl]benzylamino]-3-methylbutanamide

Abstract

(S)-2-(4′-[ 11C]methoxybiphenyl-4-sulfonylamino)-3-methylbutyric acid ([ 11C]MSMA) and N-hydroxy-(R)-2-[[(4′-[ 11C]methoxyphenyl)sulfonyl]benzylamino]-3-methylbutanamide ([ 11C]CGS 25966), carbon-11 labeled matrix metalloproteinase (MMP) inhibitors, have been synthesized for evaluation as new potential positron emission tomography (PET) cancer biomarkers. [ 11C]MSMA was prepared by appropriate precursor (S)-2-(4′-hydroxybiphenyl-4-sulfonylamino)-3-methylbutyric acid tert-butyl ester, which was synthesized in eight steps from amino acid (L)-valine in 39.4% chemical yield. This precursor was labeled by [ 11C]methyl triflate through O-[ 11C]methylation method at the hydroxyl position of biphenol under basic conditions, followed by a quick acid hydrolysis and isolated by solid-phase extraction (SPE) purification to produce pure target compound [ 11C]MSMA in 35-55% radiochemical yield, based on 11CO 2, decay corrected to end of bombardment (EOB), and 20-25 min synthesis time. [ 11C]CGS 25966 was prepared in our previous work starting from amino acid (D)-valine. The biodistribution of [ 11C]MSMA and [ 11C]CGS 25966 were determined at 45 min post iv injection in breast cancer animal models MCF-7's transfected with IL-1α implanted athymic mice and MDA-MB-435 implanted athymic mice. The results showed the uptakes of [ 11C]MSMA and [ 11C]CGS 25966 in these tumors were 0.95 and 0.42%dose/g in MCF-7's transfected with IL-1α implanted mice, 0.98 and 1.53%dose/g in MDA-MB-435 implanted mice, respectively; the ratios of tumor/muscle (T/M) and tumor/blood (T/B) were 1.21 and 1.09 (T/M, MCF-7's), 0.99 and 0.84 (T/B, MCF-7's), 1.38 and 1.27 (T/M, MDA-MB-435), 1.27 and 1.95 (T/B, MDA-MB-435), respectively. The micro-PET images of [ 11C]MSMA and [ 11C]CGS 25966 in both breast cancer athymic mice were acquired for 15 min from a MCF-7's transfected with IL-1α and/or MDA-MB-435 implanted mouse at 45 min post iv injection of 1 mCi of the tracer using a dedicated high resolution (<3 mm full-width at half-maximum) small FOV (field-of-view) PET imaging system, Indy-PET II scanner, developed in our laboratory, which showed both tumors were invisible with both tracers. The results were compared. From our results, we concluded that both [ 11C]MSMA and [ 11C]CGS 25966 might be unsuitable as PET tracers for cancer imaging.